flowchart LR
A[Colonization] --> B[Barrier Breach]
B --> C[Local Invasion]
C --> D[Bloodstream]
D --> E[Dissemination]
E --> F[End-Organ Disease]
Russell E. Lewis
Associate Professor of Infectious Diseases
Department of Molecular Medicine
University of Padua
russelledward.lewis@unipd.it
https://github.com/Russlewisbo
Slides and course materials: www.padovaid.com
Global Impact of Fungal Disease
1 million deaths annually from invasive fungal infections
Equivalent to tuberculosis mortality
Exceeds malaria deaths
Severely underrecognized and underdiagnosed
Global burden concentrated in resource-limited settings
| Type | Location | Examples |
|---|---|---|
| Superficial | Epidermis, nails | Dermatophytosis |
| Subcutaneous | Dermis, tissue | Sporotrichosis |
| Systemic (primary) | Deep organs | Histoplasmosis |
| Systemic (opportunistic) | Deep organs | Candidiasis, aspergillosis |
CRITICAL
HIGH
MEDIUM
Cell Membrane
Cell Wall
Important
Fungi share eukaryotic machinery with humans - selective toxicity is challenging!
| Agent | Candida | Aspergillus | Crypto | Mucorales |
|---|---|---|---|---|
| Fluconazole | ++ | - | ++ | - |
| Voriconazole | +++ | +++ | + | - |
| Posaconazole | +++ | +++ | + | ++ |
| Isavuconazole | +++ | +++ | + | ++ |
| Echinocandins | +++ | ++ | - | - |
| Amphotericin B | +++ | ++ | +++ | +++ |
| Drug | CSF | Eye | Urine | Lung |
|---|---|---|---|---|
| Fluconazole | +++ | +++ | +++ | ++ |
| Voriconazole | ++ | ++ | + | +++ |
| Posaconazole | + | + | - | +++ |
| Echinocandins | - | - | - | + |
| Amphotericin B | +/- | +/- | + | ++ |
Warning
Echinocandins should NOT be used for CNS, ocular, or urinary tract infections!
| Species | % of Cases | Trend |
|---|---|---|
| C. albicans | 40-60% | ↓ |
| C. glabrata | 15-25% | ↑ |
| C. parapsilosis | 10-20% | → |
| C. tropicalis | 5-10% | → |
| C. krusei | 2-5% | → |
| C. auris | Variable | ↑↑ |
Note
Azole exposure drives shift toward non-albicans species
Host Factors
Healthcare Exposures
flowchart LR
A[Colonization] --> B[Barrier Breach]
B --> C[Local Invasion]
C --> D[Bloodstream]
D --> E[Dissemination]
E --> F[End-Organ Disease]
Diagnostic Challenge
Blood cultures detect only ~50% of invasive candidiasis cases
| Test | Sensitivity | Specificity | Turnaround |
|---|---|---|---|
| β-D-glucan | 75-80% | 80% | Same day |
| T2Candida | 91% | 99% | 3-5 hours |
| Candida PCR | 85-95% | 90-95% | Variable |
Tip
Combining blood cultures + BDG increases sensitivity to >90%
flowchart TD
A[Candidemia] --> B{Hemodynamic Status}
B -->|Unstable| C[Echinocandin]
B -->|Stable| D{Prior Azole Exposure?}
D -->|Yes| C
D -->|No| E[Fluconazole Option]
C --> F[Species ID + Susceptibility]
E --> F
F --> G[De-escalation if appropriate]
Central Venous Catheter Removal
Warning
Delay in catheter removal = increased mortality
| Species | Fluconazole | Echinocandins | Clinical Note |
|---|---|---|---|
| C. albicans | S ≤2 | S ≤0.25 | Usually susceptible |
| C. glabrata | SDD ≤32 | S ≤0.12 | Check both! |
| C. krusei | Intrinsic R | S | Never use fluconazole |
| C. parapsilosis | S ≤2 | Higher MICs | Fluconazole often preferred |
| C. auris | Often R | Variable | Test everything |
Important
If C. auris suspected → Contact infection control immediately
Sub-Saharan Africa bears the greatest burden
| Species | Primary Host | Geography | Environment |
|---|---|---|---|
| C. neoformans | Immunocompromised | Worldwide | Soil, bird droppings |
| C. gattii | Immunocompetent + compromised | Pacific NW, Australia, Tropics | Eucalyptus trees |
Note
C. gattii can cause disease in immunocompetent hosts!
Virulence Factors:
India ink preparation showing encapsulated yeast
Critical Complication
Opening pressure >25 cm H₂O is associated with poor outcomes
Mechanism:
Management:
| Test | Sensitivity | Specificity | Notes |
|---|---|---|---|
| CSF CrAg (LFA) | 99% | 99% | Point-of-care, rapid |
| Serum CrAg | 99% | 99% | Precedes symptoms |
| India ink | 75-85% | >95% | Less sensitive |
| Culture | 95% | 100% | Takes 3-7 days |
Tip
Screen all HIV+ patients with CD4 <100 for serum CrAg
| Parameter | Typical Finding |
|---|---|
| Opening pressure | Elevated (often >25 cm H₂O) |
| WBC | Elevated (lymphocyte predominant) |
| Glucose | Low |
| Protein | Elevated |
| CrAg | Positive |
Landmark Study (NEJM 2022)
Single high-dose liposomal amphotericin B non-inferior to standard 7-day amphotericin B
Regimen:
Results:
Preferred (AMBITION):
Alternative:
Poor outcomes associated with:
Immune Dysfunction:
Normal:
Immune Hyperactivity:
| Species | Frequency | Clinical Significance |
|---|---|---|
| A. fumigatus | 70-80% | Most common; azole resistance emerging |
| A. flavus | 10-15% | Sinusitis; aflatoxin producer |
| A. niger | 5-10% | Otomycosis; aspergillomas |
| A. terreus | 2-5% | Amphotericin B resistant |
| A. nidulans | Rare | CGD-associated |
Aspergillus Morphology:
Host Defenses:
Note
Immunocompetent hosts clear thousands of conidia daily without disease
Classic High-Risk:
Emerging Risk Groups:
Pathology:
Diagnostics:
| Day | Pathology | CT Finding |
|---|---|---|
| 0-3 | Hyphal invasion | Macronodule ± halo |
| 5-7 | Hemorrhage, infarction | Dense consolidation |
| 10-12 | Extensive necrosis | Hypodense sign |
| 15-18 | Neutrophil recovery | Air-crescent sign |
Clinical Pearl
The halo sign (ground-glass surrounding a dense nodule) is relatively specific for angioinvasive mold infection in the first week in neutropenic patients
Nodule with Halo Sign
Centrilobular Nodules
| Sample | Cutoff | Sensitivity | Specificity |
|---|---|---|---|
| Serum | ≥0.5 ODI | 70-80% | 85-90% |
| BAL | ≥1.0 ODI | 85-90% | 90-95% |
Warning
False Positives:
Culture and Histopathology:
Biomarkers:
If NO Prior Mold-Active Prophylaxis
Voriconazole (preferred by IDSA)
Alternatives:
If Receiving Posaconazole Prophylaxis
Switch to a different class initially:
Important
If resistance is suspected or confirmed, treat with liposomal amphotericin B
Duration:
Prognosis Depends On:
Twitter poll of ID specialists:
Important
Why so scary?
Environmental Sources:
Morphology:
Metabolic:
Immunologic:
Others: Trauma, burns, combat injuries, COVID-19
| Genus | Features |
|---|---|
| Rhizopus | Most common (especially R. arrhizus) |
| Mucor | Less common but significant |
| Lichtheimia | Common in immunocompromised |
| Rhizomucor | More aggressive |
| Cunninghamella | Disseminated disease; worst prognosis |
flowchart LR
A[Spore Inhalation] --> B[Macrophage Engulfment]
B -->|Impaired by steroids| C[Hyphal Growth]
C --> D[Iron Acquisition]
D -->|Promoted by DKA, acidosis| E[Angioinvasion]
E --> F[Thrombosis & Necrosis]
Important
Deferoxamine acts as a fungal siderophore - increases risk!
Deferasirox does NOT increase risk - use this for iron chelation
Progression:
Rapid progression with nasal bridge necrosis
Imaging Pearl
Loss of enhancement of the turbinates on contrast MRI indicates devitalized tissue - highly suggestive of mucormycosis in the right clinical context
CT Features:
Reverse halo: ground-glass center with surrounding consolidation
Critical Point
β-D-glucan and galactomannan do NOT detect Mucorales!
Diagnostic Approach:
Initial:
Step-down:
Note
Echinocandins and voriconazole have NO activity against Mucorales
Important
Don’t delay surgery for imaging or culture results in high-risk patients
| Formulation | ≥2-fold SCr Increase |
|---|---|
| Amphotericin B deoxycholate | 26% |
| Liposomal AMB | 10% |
Mechanism:
| Toxicity | Agent(s) |
|---|---|
| Hepatotoxicity | All (especially voriconazole) |
| QTc prolongation | All (less with isavuconazole) |
| Visual disturbances | Voriconazole |
| Phototoxicity/skin cancer | Voriconazole (chronic) |
| Peripheral neuropathy | Itraconazole > voriconazole |
| Adrenal suppression | Itraconazole, posaconazole |
Triazole Monitoring
Contact: Russell E. Lewis, PharmD, FCCP
Selected References:
The following slides contain additional reference material and case examples.
Clinical Scenario:
55-year-old male, recent abdominal surgery, TPN, central line, develops fever on antibiotics.
Blood culture positive for Candida glabrata
Clinical Scenario:
32-year-old male, newly diagnosed HIV (CD4 45), 2-week headache, confusion, fever.
LP: OP 32 cm H₂O, CrAg positive, WBC 15 (lymphs)
Management priorities?
Clinical Scenario:
60-year-old female, AML induction, neutropenic day 18, persistent fever, new pulmonary nodules with halo sign.
Questions:
Clinical Scenario:
58-year-old male, DKA, facial pain, periorbital swelling, nasal eschar.
Immediate actions:
Proven Invasive Fungal Infection:
Requires ALL THREE:
Key CYP450 Interactions:
| Azole | CYP Inhibition | Major Interactions |
|---|---|---|
| Voriconazole | 3A4, 2C19, 2C9 | Calcineurin inhibitors, sirolimus |
| Posaconazole | 3A4 | Calcineurin inhibitors, sirolimus |
| Isavuconazole | 3A4 | Calcineurin inhibitors |
| Fluconazole | 3A4, 2C9 | Warfarin, calcineurin inhibitors |
| Drug | Loading | Maintenance |
|---|---|---|
| Fluconazole | 800 mg | 400 mg daily |
| Voriconazole | 6 mg/kg q12h × 2 | 4 mg/kg q12h |
| Posaconazole DR | 300 mg q12h × 2 | 300 mg daily |
| Isavuconazole | 200 mg q8h × 6 | 200 mg daily |
| Caspofungin | 70 mg | 50 mg daily |
| Micafungin | - | 100 mg daily |
| Anidulafungin | 200 mg | 100 mg daily |
| L-AMB | - | 3-5 mg/kg daily |